a) We have completed several studies using idazoxan as a pharmacological probe of alpha-2 receptor function. While the central and peripheral responses we have observed are consistent with and likely attributable to alpha-2 receptor blockade, idazoxan also has high affinity for imidazoline receptors. To determine whether these effects are due to alpha-2 blockade we have initiated several studies in volunteers of the acute effects of ethoxyidazoxan, a structural analogue of idazoxan that has no affinity for imidazoline sites. We have now studied doses up to 15 ug/kg in our dose response study of ethoxyidazoxan. We find that the drug is well tolerated and that doses of 9 to 12 ug/kg produce effects of the same magnitude as 200 ug/kg of idazoxan. Responses include modest increases in blood pressure, body temperature, modest reductions in plasma glucose, and dose dependent increases in plasma norepinephrine. b) To similarly address the possible interaction with imidazoline sites during brain metabolic studies, we are currently completing an FDG PET study with two different doses of ethoxyidazoxan (9 ug/kg and 12 ug/kg). Preliminary results suggest a substantial overlap in metabolic effects seen after the two drugs, although the lower dose of ethoxyidazoxan is more likely to produce diffuse increases in brain metabolism. c) Pharmacological manipulation of alpha-2 receptors has been shown in a number of pre-clinical and clinical studies to enhance performance on selected attention and memory tasks. We are investigating this phenomena with ethoxyidazoxan in a collaboration with Francois Lalonde, comparing performance on the Stroop nd Treisman selective attention tasks after active drug or placebo.